The present invention relates to a percutaneous absorption preparation, more particularly to a reservoir type percutaneous absorption preparation wherein at the time of preservation a permeation controlling film is in-permeable to medicines and the medicines exist stably in a medicine storage layer and wherein at the time of application of the preparation, as the permeation controlling film is plasticized by moisture evaporating from the skin, the medicines move into a layer of an adhesive and are absorbed through the skin.
As a conventional percutaneous absorption preparation there is reported a system in which a medicine storage layer and a medicine activating agent are divided by a medicine in-permeable film and, with the in-permeable film being made destroyed or burst by the user upon application, the medicine moves to a layer of an adhesive by the aid of the activating agent and is absorbed through the skin(JP-A-H1-85912). This system, however, leads to lowered compliance of the patient side because it needs the work of the destroying or bursting the user has to do upon application, and moreover has the defect that the manufacturing method is complicated. Further, the system poses the problem in the case of a patch preparation in which the medicine is contained in the layer of an adhesive, in that it lacks long-term preservability and introduces the lowering of the medicine content or eventually reduced therapeutic effect because the medicine gradually decomposes or deteriorates if the medicine is an unstable compound in the layer of an adhesive.
The object of the present invention is to provide a percutaneous absorption preparation which is simple in its use and manufacturing method, and which, even when the medicine is an unstable compound in the layer of an adhesive, makes the medicine preservative stably by restraining its decomposition and deterioration during preservation and which allows the medicine to move to the layer of adhesive and the skin and to be absorbed through the skin at the time of application of the preparation.
The inventors studied earnestly to solve the above problem and found as a result that the problem concerned was solved by the percutaneous absorption preparation which comprised a supporting body, a medicine storage layer, a permeation controlling film, a layer of an adhesive and a release liner and which was featured in that the above permeation controlling film was plasticized by moisture volatilized from the skin upon application of that preparation, thus achieving the present invention.
Namely, the present invention includes the following inventions.
(1) A percutaneous absorption preparation comprising a supporting body, a medicine storage layer, a permeation controlling film, a layer of an adhesive and a release liner, which is characterized in that the permeation controlling film is plasticized by moisture volatilized from the skin at the time of application of the preparation.
(2) A percutaneous absorption preparation according to the above (1), wherein the permeation controlling film is a water-soluble polymer.
(3) A percutaneous absorption preparation according to the above (2), wherein the water-soluble polymer is poly(vinyl alcohol).
(4) A percutaneous absorption preparation according to the above (1), wherein the medicine storage layer is formed by a medicine, or a medicine and a vehicle.
(5) A percutaneous absorption preparation according to the above (4), wherein the medicine is water-soluble.
(6) A percutaneous absorption preparation according the above (4), wherein the vehicle is a water-disintegrative substance.
(7) A percutaneous absorption preparation according to the above (1), wherein the supporting body has a water-vapor permeability of 100 g/m2 or less at the condition of 40xc2x0 C. and 24 hours.
(8) A percutaneous absorption preparation according to the above (1), wherein the adhesive has a water-vapor permeability of 100 g/m2 or more at the condition of 40xc2x0 C. and 24 hours.
(9) A percutaneous absorption preparation according to the above (1), wherein the therapeutic medicine is nicorandil, dopamine hydrochloride or eperisone hydrochloride.
The present invention is explained in detail in the following.
The percutaneous absorption preparation of the present invention is one which comprises a supporting body, a medicine storage layer, a permeation controlling film, a layer of an adhesive and a release liner and which is characterized in that the above-mentioned permeation controlling film is plasticized by moisture evaporating from the skin at the time of application of the preparation.
The word xe2x80x9cplasticizexe2x80x9d means xe2x80x9cto make a substance prone to cause plastic deformation or plastic flow by an external forcexe2x80x9d, and in the case of the invention it means that the permeation controlling film gives rise to plastic flow because of its absorbing moisture and the medicine activated by moisture permeates, dissolves, disperses or diffuses into the permeation controlling film.
In the percutaneous absorption preparation of the present invention, it is necessary that the permeation controlling film is located between the medicine storage layer and the layer of adhesive and plasticized by moisture volatilized from the skin upon application of the preparation. Thus, the medicine, or the medicine and vehicle permeates, dissolves, disperses or diffuses into the permeation controlling film and moves to the layer of adhesive, and the medicine is absorbed through the skin. As the permeation controlling film any component may be used without limitation as long as it is plasticized by moisture evaporating from the skin and allows the permeation of the medicine when the preparation is applied. As such permeation controlling films there are enumerated water-soluble polymers, preferably synthetic polymers such as poly(vinyl alcohol) and poly(vinylpyrrolidone), polysaccharides such as soluble starch, dextrin, cellulose, methylcellulose and carboxymethylcellulose, natural polymers such as corn starch, sodium alginate, gum arabic, gelatin and pullulan, and inorganic polymers such as sodium polyphosphate and water glass. Most preferred is poly(vinyl alcohol).
In the percutaneous absorption preparation of the present invention, the medicine storage layer is formed by a medicine, or a medicine and a vehicle (excipient).
As the vehicle preferably enumerated are water-disintegrative substances, though there is no limitation as long as it is ones generally used. Here, xe2x80x9cwater-disintegrative substancexe2x80x9d indicates xe2x80x9ca substance which functions as a vehicle at the time of preparing the medicine storage layer and as a disintegrative agent in the presence of moisture at the time of applying the preparation.xe2x80x9d Such water-disintegrative substances include, for example, saccharides such as glucose, lactose, sucrose, starch, soluble starch and methylcellulose, polyethyleneglycols and polysolbates.
As the therapeutic medicine used for the medicine storage layer, any may be employed without limitation as long as it is absorbed percutaneously. Preferable are amine type therapeutic medicines such as nicorandil, dopamine hydrochloride and eperisone hydrochloride.
Further, as the therapeutic medicine there are enumerated non-steroidal anti-inflammatory drugs, steroid type anti-inflammatory drugs, antiarrhythmic drugs, antitumor agents, hypnotics, psychotropic drugs, local anesthetic drugs, cardiotonic drugs, antibiotics, antituberculosis drugs, analgesic agents, muscular relaxants, anti-asthma drugs, anti-cholinergic agents, vasodilators, antihypertensive agents, antihistamines, cholinergic agents and angiotensin invertase inhibitors.
It is needed that the therapeutic medicine used in the percutaneous absorption preparation of the present invention permeates, dissolves, disperses or diffuses into the permeation controlling film that has been plasticized by moisture volatilized from the skin.
The medicine storage layer may incorporate, if necessary, additives such as kaolin, talc, bentonite, titanium oxide, calcium bicarbonate, aluminum sulfate, silicic anhydride, zinc oxide, silica and alumina; antioxidants such as BHT, BHA, guaiacol ester and nordihydroguaiaretic acid; and absorption accelerators such as crotamiton, benzyl alcohol, ethanol, diethyl sebacate and isopropyl myristate.
To retain the medicine storage layer in the percutaneous absorption preparation of the present invention, the upper part or outside of the medicine-storage layer is needed to be covered by a supporting body.
Although the supporting body in the percutaneous absorption preparation of the present invention is not limited to a particular material as long as it is in-permeable to the medicine and water-vapor, preferred is one that has a water-vapor permeability of 100 g/m2 or less after 24 hours at 40xc2x0 C. (determined according to JIS Z0208,Testing Method of Water-vapor Permeability of Moisture-proof Packaging Material (Cup Method)). Examples of such supporting body include a sheet and a film of poly(ethylene terephthalate), polyethylene and polypropylene, a laminated sheet made by using two or more of the above and a laminated sheet of the above film and sheet with a nonwoven fabric or woven fabric.
The adhesive in the percutaneous absorption preparation of the present invention is not limited to a particular component as long as it is attachable to the skin and permeable to water-vapor, but preferable is such that has a water-vapor permeability of 100 g/m2 or more after 24 hours at 40xc2x0 C. As such adhesives there are enumerated, for example, acrylic adhesives, rubber type adhesives and silicone type adhesives. The layer of adhesive may incorporate, other than the above adhesives, according to necessity, adhesion providing agents such as rosin resin, terpene resin, aromatic hydrocarbon resin, aliphatic hydrocarbon resin, petroleum resin, ester gum, fat-like phenol resin; softening agents such as isopropyl myristate, oleyl oleate, polybutene, isopolybutene, liquid paraffin, squalene, silicone oil, olive oil, soybean oil, rape seed oil, coconut oil and beef tallow; additives such as kaolin, talc, bentonite, titanium oxide, calcium bicarbonate, aluminum sulfate, silicic anhydride, zinc oxide, silica and alumina; antioxidants such as BHT, BHA, guaiacol ester and nordihydroguaiaretic acid; and absorption assistants such a scrotamiton, benzyl alcohol, ethanol, diethyl sebacate and isopropyl myristate.
The release liner in the percutaneous absorption preparation of the present invention is not limited particularly as long as it is a material soft and in-permeable to the medicine and is exemplified by a film of polyethylene, polyester and the like which is coated with a silicone resin as releasing agent.
One mode of the percutaneous absorption preparation of the present invention can be illustrated by what has the structures shown in FIGS. 1(A) and (B).
In FIGS. 1(A) and (B), the numeral 1 denotes a supporting body, 2 a medicine storage layer, 3 a permeation controlling film, 4 a layer of adhesive and 5 denotes a release liner.
In the percutaneous absorption preparation shown in FIG. 1, supporting body 1 is located on the upper part or outside of medicine storage layer 2 and performs the function of retaining medicine storage layer 2. Permeation controlling film 3 is located on the lower part of medicine storage layer 2 and takes the function of controlling the permeation of the medicine into the layer of adhesive 4. The layer of adhesive 4 is located on the lower part of permeation controlling film 3 and performs the function of affixing the patch preparation to the skin. Upon using the patch preparation, release liner 5 located on the lower part of the layer of adhesive 4 is removed and the preparation is applied to the skin.
The medicine contained in medicine storage layer 2 is absorbed through the skin via permeation controlling film 3 and layer adhesive 4.
This is specification includes part or all of the contents as disclosed in the specification of Japanese Patent Application No. 11(1999)-165693, which is a base of priority claim of the present application.